sexta-feira, 11 de maio de 2012

Caso NEJM- Mulher 43 anos com febre e rash generalizado


Case 14-2012 — A 43-Year-Old Woman with Fever and a Generalized Rash

Dr. Sarah Gee (Dermatology): A 43-year-old woman was admitted to the hospital because of fever and a generalized rash.
The patient had a history of atopic dermatitis and had been in her usual health until approximately 1 week before admission, when a painful, pruritic rash developed on her chin, neck, and chest; it gradually spread to involve her entire body, sparing the palms, soles, and genitalia. Four days before admission, she went to the emergency department at another hospital. She reported that the rash was similar to but more severe than her usual atopic dermatitis, which was not painful. Prednisone and hydroxyzine were administered, and she was discharged home. The next day, the rash persisted, chills developed, and the temperature reportedly rose to 39.4°C. The patient returned to the other hospital. On examination, the temperature was 38.6°C, and the blood pressure, pulse, and oxygen saturation were normal. A diffuse, erythematous rash with vesicles, pustules, and excoriations involved the forehead, nose, lips, chin, periorbital areas, chest, back, arms, and legs and spared the palms, soles, and part of the cheeks. The complete blood count was reportedly normal.
The patient was admitted to the other hospital, and clindamycin, hydromorphone, hydroxyzine, acetaminophen, and intravenous fluids were administered; white petrolatum ointment was applied to dry and cracking areas. The next day, a dermatologic consultation was obtained, and a skin biopsy and culture were performed. A chest radiograph was normal. During the second night, the temperature rose to 39.6°C, and sloughing of the skin occurred with pressure. Gram's staining of the skin-biopsy specimen reportedly showed no neutrophils or organisms; culture of the skin revealed a heavy growth of Staphylococcus aureus. Infectious disease consultation was obtained; the administration of clindamycin was stopped, and vancomycin and acyclovir were begun. The blood pressure ranged from 110 to 130 mm Hg systolic and from 50 to 69 mm Hg diastolic, and the oxygen saturation was 95 to 100% while the patient was breathing ambient air. Blood cultures were sterile. Other laboratory-test and culture results were pending. The patient was transferred to this hospital. Medications on transfer included vancomycin, acyclovir, hydromorphone, hydroxyzine, acetaminophen, and fluoxetine, with albuterol as needed.
The patient and her boyfriend reported that the lesions had first appeared vesicular, were followed by erosions, and ultimately became small, round, open, and painful areas, with larger eroded areas on the chest and limbs; this course differed from her usual flares of atopic dermatitis. She reported mild eye irritation, tearing, and visual blurring. Her history of asthma and atopic dermatitis began in childhood. Three years earlier, a flare of atopic dermatitis had occurred after treatment with trimethoprim–sulfamethoxazole for a urinary tract infection; the dermatitis resolved after the administration of oral glucocorticoids and hydroxyzine. Examination of a skin-biopsy specimen obtained at that time reportedly showed atopic dermatitis. Recurrences since then were associated with stress, menses, and allergens, including pet hair, and responded to glucocorticoids and hydroxyzine. The patient had no history of cold sores. She had depression and anxiety and several years earlier had had cervical intraepithelial neoplasia. Medications before admission included fluoxetine, lorazepam, albuterol (as needed), and triamcinolone ointment. She was allergic to penicillin (reaction unknown) and trimethoprim–sulfamethoxazole and had seasonal and environmental allergies. She had had a positive test for tuberculosis 20 years earlier, for which she had taken isoniazid for 9 months. Testing for the human immunodeficiency virus was reportedly negative in the past. She had moved to New England 2 weeks earlier and lived with her boyfriend, who owned a cat and who had a history of cold sores but had had none recently. Her mother had died of ovarian cancer; multiple paternal relatives had atopic dermatitis. She smoked five cigarettes a day and did not drink alcohol or use illicit drugs.
On examination, the patient was extremely uncomfortable. The blood pressure was 146/62 mm Hg, the pulse 109 beats per minute, the temperature 39.3°C, the respiratory rate 22 breaths per minute, and the oxygen saturation 99% while she was breathing ambient air. Pain was severe and increased with any small movements or pressure on the skin. There was mild expiratory wheezing in the right lung fields, with decreased basilar breath sounds bilaterally. A diffuse rash involved nearly all areas of her body, including the scalp, face, neck, torso, and limbs; the palms, soles, and genitalia were spared. There were scaly, erythematous plaques with small, round, “punched out,” and crusted erosions (approximately 1 mm in diameter) and scattered larger erosions with scalloped borders, with larger confluent areas on the chest, arms, and legs; lesions were less prominent on the posterior trunk, buttocks, and posterior knees. Blood levels of glucose, bilirubin, magnesium, amylase, alkaline phosphatase, alanine aminotransferase, globulin, and platelets were normal, as were the erythrocyte sedimentation rate and results of renal-function tests; other test results are shown in Table 1
TABLE 1Laboratory Data.
. Urinalysis showed yellow turbid fluid, with 2+ ketones and albumin, 3 to 5 red cells, 5 to 10 white cells, and a few squamous cells per high-power field, and was otherwise normal. A chest radiograph was normal. The patient was admitted to the burn service, and dermatologists and ophthalmologists were consulted.
Morphine was administered intravenously by a patient-controlled device, other narcotic analgesic agents were administered orally, and vancomycin and acyclovir were continued. Open areas of the skin were covered with nonadherent, silicone fine-mesh dressings and antimicrobial barrier dressings. During the first 3 days, the temperature rose to 39.6°C intermittently, with tachycardia (up to 130 beats per minute). Ophthalmologic examination revealed corneal epithelial staining (in areas measuring approximately 0.5 mm) in both eyes, without a dendritic pattern; ophthalmic lubricant ointment and moxifloxacin ophthalmic drops were administered. The patient was able to consume liquids and small amounts of solid foods with no adverse effects, was hemodynamically stable, and had adequate urine output. Lesions on the upper chest and face became coalescent, forming large erosions with scalloped borders. Cultures of blood and urine were sterile, a nasal specimen was negative for evidence of methicillin-resistant S. aureus, a rectal specimen was negative for vancomycin-resistant enterococcus, and a sputum culture grew mixed normal respiratory flora. The administration of dalteparin was begun.
A diagnostic test result was received.


Dr. Bonnie T. Mackool: I am aware of the diagnosis in this case. This woman had a long-standing skin disorder and recent symptoms, including pain and fever, that were different from previous symptoms. She initially reported a diffuse erythematous eruption, with vesicles and pustules; erosions were seen on examination. Table 2TABLE 2Differential Diagnosis of Rash with Vesicles, Pustules, and Erosions. lists cutaneous eruptions that are characterized by vesicles, pustules, erosions, or a combination of these.

Kaposi's Varicelli form Eruption

The development of cutaneous pain in a patient with a preexisting skin disorder should immediately raise the possibility of Kaposi's varicelliform eruption (KVE), also known as eczema herpeticum. In this disorder, a viral infection, usually caused by herpes simplex virus type 1 (HSV-1) or, less often, type 2 (HSV-2), is superimposed on inflamed skin, typically atopic dermatitis,1 although other viruses may cause the same syndrome and other dermatoses may be infected.2-4 HSV, when inoculated into a generalized rash, may spread rapidly and is potentially life-threatening5,6; immediate treatment is therefore imperative (e.g., intravenous acyclovir, as in this case) while diagnostic confirmation is pending.7Other infectious and noninfectious causes of a rash such as that seen in this patient should also be considered.

Infections That Can Resemble KVE


A characteristic rash develops in patients with smallpox (i.e., variola virus infection). Lesions are initially macular and progress together in the same stage to papules, vesicles, and pustules,8 first on the face, hands, and forearms and then on the trunk, and may involve the mucosae. Papules, vesicles, and pustules are tense and firm and monomorphic in any one area of skin.9 In this patient, the lesions were monomorphic in shape and size; however, unlike the lesions in smallpox, vesicles, pustules, and erosions were visible at the same time and in different stages of development. Moreover, the erosions with scalloped borders seen in this patient are not typical of smallpox. The last known naturally occurring case of smallpox was in 1977, and a fatal laboratory-acquired case occurred in 1978. The virus exists in two laboratories, and the fear of biowarfare has led to a smallpox-vaccination program for military personnel. The likelihood of smallpox in this patient is low.

Varicella and Herpes Zoster

Varicella–zoster virus is a herpesvirus that is the cause of an acute generalized disease (varicella, or chickenpox) and a delayed dermatomal eruption (herpes zoster, or shingles); in both varicella and herpes zoster, patients present with vesicles that may become pustular. Also, in an immunocompromised host, herpes zoster may generalize. Itching and fever are common in both varicella and herpes zoster, and pain is typically associated with localized herpes zoster eruptions. Adults who have escaped early infection and are unvaccinated can acquire the acute generalized infection, so-called chickenpox. We do not know this patient's history of early childhood diseases or vaccinations, but she had no history of an exposure that would suggest acute varicella infection; also, her eruption was not dermatomal in distribution and thus did not suggest reactivation.

Staphylococcal Infection

Bullous impetigo may occur when S. aureus is inoculated into areas of dermatitis. A common scenario occurs in children with atopic dermatitis who have a bout of chickenpox — scratching the pruritic varicella lesions inoculates S. aureus into the lesions. Patients with severe contact dermatitis superinfected by the staphylococcal bacteria may present with vesicles, pustules, and fever. Staphylococcal infections do not have the characteristic monomorphic and scalloped-border erosions and hemorrhagic features that were seen in this patient. Lesions of KVE are frequently superinfected with S. aureus (impetiginized), and the yellow crusting of impetigo can obscure the diagnosis of KVE.

Noninfectious Disorders That Can Resemble KVE

Pustular Psoriasis

Patients with pustular psoriasis usually have known psoriasis and typically present with fever, leukocytosis, malaise, and a sterile pustular eruption. Waves of these signs and symptoms alternate with periods of stability and improvement. Although this patient's underlying skin disease could be psoriasis rather than eczema, vesicles are not present in pustular psoriasis.

Drug Hypersensitivity

Patients with acute generalized exanthematous pustulosis (a hypersensitivity reaction to drugs) may present with fevers and tender pustules. Vesicles are not present, and neither are the erosions that were seen in this patient. Patients with linear IgA bullous dermatosis, which is a reaction to certain medications, including vancomycin, typically present with small vesicles and erythema. Drug-induced vesicular or papular eruptions may or may not be associated with fever and other systemic symptoms. A variety of drugs may cause the DRESS syndrome (drug reaction with eosinophilia and systemic symptoms). Coalescent erosions with scalloped borders and hemorrhagic crusting are not features of drug reactions, and this patient did not have eosinophilia.

Erythema Multiforme and Toxic Epidermal Necrolysis

Bullous erythema multiforme may initially be vesicular and progress to pustules and erosions, as seen in this case, and the skin may be tender. Erythema multiforme may be due to drugs and infections (e.g., herpes simplex or Mycoplasma pneumoniae) but is also frequently idiopathic. Toxic epidermal necrolysis is almost always due to a drug and presents with vesicles; as denudation occurs, cutaneous pain is prominent. Severe mucosal involvement is characteristic and was not seen in this case. The erosions are characterized by diffuse dermal denudation; they do not appear punched out or monomorphic, as they did in this case.

Other Noninfectious, Immune-Mediated Disorders

Bullous lupus erythematosus may cause round denuded areas but lacks the hemorrhagic erosions with scalloped borders seen in this case. Bullous pemphigoid and herpes gestationis may be predominantly vesicular and resemble the vesicular phase of KVE, but this patient was not pregnant and had no other clinical features of bullous pemphigoid.
Purpuric vesicles or pustules may occur in vasculitides, such as the immune-mediated vasculitis Henoch–Schönlein purpura; lesions may pass through a vesicular and pustular phase caused by epidermal ischemia. Fever, abdominal pain, arthritis, proteinuria, and hematuria may precede or accompany the rash, and other organs may be involved. Petechiae, which are characteristic of Henoch–Schönlein purpura, were not seen in this patient, and she did not have the other systemic manifestations of Henoch–Schönlein purpura.

History and Cutaneous Morphologic Features of KVE

The history and clinical features of this case overwhelmingly favor the diagnosis of KVE. The classic initial cutaneous manifestation of KVE is monomorphic vesicles that become pustular, often with a hemorrhagic and erosive component at later stages; erosions appear to be punched out or well demarcated, as seen in this patient.4 The erosive lesions tend to coalesce, creating large lesions with scalloped borders (Figure 1AFIGURE 1
Clinical Photographs of the Patient's Skin.
). Fever, malaise, and lymphadenopathy are often present; this patient was febrile and felt unwell. The characteristic round or oval individual lesions and round coalescent borders were seen in this patient (Figure 1B). The distribution of these lesions, however, was unusually extensive (Figure 1C).

Other Viruses That Can Cause KVE

Infections with viruses other than HSV, mainly vaccinia virus and coxsackievirus A16, may cause KVE.1-3,10

Vaccinia Virus

In patients with atopic dermatitis or other dermatoses, KVE may develop from infection with vaccinia virus, which is life-threatening and may be clinically indistinguishable from KVE due to infection with HSV.2,11 The U.S. military began a smallpox vaccination program in 2002 using the vaccinia virus; patients with atopic dermatitis are excluded from vaccination because of their risk of KVE. Despite this precaution, accidental exposures of persons with atopic dermatitis to recently vaccinated persons have occurred. Patients such as this one with a presentation that raises suspicion for KVE should therefore be questioned about contacts with recently vaccinated military personnel.

Coxsackievirus A16

Hand, foot, and mouth disease, caused by coxsackievirus A16, occurs most commonly in children. It is characterized by macular and then vesicular eruptions on the hands and feet, which appear 1 to 2 days after a prodrome of fever, sore throat, and malaise.12 Disseminated skin disease after the initial distal vesicular eruption, with features characteristic of KVE, has been reported in a child with atopic dermatitis.3

Predisposing Skin Conditions for KVE

The development of KVE is more likely in persons with atopic dermatitis than in those with other inflammatory skin disorders.10 This predisposition is attributed both to abnormalities in the immune system13-16– and to defects in the barrier function of the epidermis that render such persons more susceptible to infection.14 Psoriasis,17 seborrheic dermatitis,4 rosacea,18 tinea cruris,19 Grover's disease (transient acantholytic dermatosis),20 cutaneous T-cell lymphoma,21-23– Hailey–Hailey disease (familial benign pemphigus),24 pemphigus foliaceous,24 Darier's disease (follicular keratosis),25 laser resurfacing,26 ichthyosis,27 lichen sclerosus et atrophicus (case observation by the first author), pityriasis rubra pilaris,28 contact dermatitis,29 and burns30 have all been described as substrates for the development of KVE.
This patient had a diagnosis of atopic dermatitis. Examination of her skin on admission (Figure 1B) showed scaly areas with well-demarcated borders, raising the possibility that the underlying dermatosis was psoriasis. She had no other signs of psoriasis, such as nail or scalp abnormalities or intergluteal erythema. Patients with psoriasis are at lower risk for the development of KVE than are patients with atopic dermatitis.17 This patient's history of asthma and the responsiveness of her rash in the past to glucocorticoids and hydroxyzine, as well as the strong family history of atopic dermatitis, favor a diagnosis of atopic dermatitis.

Diagnostic Testing

The diagnosis of KVE can be made by Tzanck testing of vesicular fluid, direct fluorescent antibody staining of vesicular fluid, or viral culture. Most rapid are the bedside Tzanck test and direct fluorescent antibody testing.31 In the erosive stage, culture of the vesicular fluid is most reliable for making a diagnosis, but this takes days. If the diagnosis of KVE is suspected, it is imperative to initiate treatment while awaiting culture results, as was done in this case. It is important to avoid inoculation of the virus to new areas through wiping or touching. Skin-biopsy specimens are not the diagnostic tool for KVE, but examination of a specimen could elucidate the type of preexisting dermatitis if it is uncertain, as was the case in this patient.31 Assuming this patient did not have exposure to recently vaccinated military personnel, HSV is the most likely pathogen; HSV-1 is more common than HSV-2. Although her boyfriend did not have a known herpes labialis lesion at the time of her illness, he could have been the source of her exposure; in one study, 68% of patients with KVE reported being in the company of relatives or close friends with HSV infections just before symptoms of KVE began.10


This patient with a history of a preexisting dermatosis had cutaneous pain, fever, vesicles, pustules, and erosions, features characteristic of KVE. Her underlying diagnosis is most likely atopic dermatitis. The extent of the eruption predisposes her to bacterial sepsis and overwhelming viremia, the two main causes of death associated with KVE. The mortality rate associated with KVE is difficult to estimate, since patients with limited involvement may clear without treatment and patients may be treated outside of large hospitals in which data collection occurs. For hospitalized patients in 1982, the mortality rate was estimated between 2% and 10%, but this was in an era when treatment with acyclovir was relatively new.4
The results of several diagnostic tests were received for this patient. These included examination of the punch-biopsy specimen of the skin obtained at the other hospital, direct fluorescent antibody testing of a smear of skin obtained from a lesion on admission to this hospital, and another punch-biopsy specimen of the skin obtained on the third day, to clarify whether the underlying dermatosis was atopic dermatitis or psoriasis.


Kaposi's varicelliform eruption due to herpes simplex virus infection.


Dr. Rosalynn M. Nazarian: A 4-mm punch-biopsy specimen of a skin lesion on the left anterior shoulder was obtained at the other hospital 3 days before admission to this hospital. Review of the specimen revealed a vesicular dermatitis with epidermal acantholysis, ulceration, and multinucleated keratinocytes, with clear (“glassy”) nuclei, chromatin margination, and nuclear molding, indicative of viral inclusions involving both the epidermis and the follicular epithelium (Figure 2A
FIGURE 2Skin-Biopsy Specimens.). A diagnosis of herpesvirus infection was made.
A 3-mm punch-biopsy specimen of the skin from the dorsal surface of the left hand obtained at this hospital in order to better characterize the underlying dermatosis revealed mild regular acanthosis and both hyperkeratosis and parakeratosis, with diminution of the granular-cell layer (Figure 2B). These features are characteristic of psoriasiform dermatitis and are consistent with psoriasis. However, during acute disease flares resulting in erythroderma, a condition characterized by diffuse exfoliative erythema, as was seen in this patient, the nature of the underlying dermatologic disease can be difficult to determine; the pathological changes are not specific in 7 to 34% of cases.32,33
The histopathological differential diagnosis of KVE includes disorders characterized by acantholysis, blister formation, or both (e.g., pemphigus vulgaris, impetigo, Darier's disease, and Hailey–Hailey disease) and disorders characterized by intracytoplasmic viral inclusions (e.g., molluscum contagiosum, milker's nodule, and orf). Intranuclear inclusions and multinucleated giant keratinocytes in a patient with acantholysis and vesiculation are unique to herpesvirus infection. Histologic differentiation among HSV-1, HSV-2, and varicella–zoster virus is not possible.31
Direct fluorescent antibody testing of the smears of vesicular fluid obtained on admission was positive for HSV-1. The virus was subsequently grown from a culture of this lesion.


Dr. Jeremy Goverman: Our primary role at the burn center is to care for patients with thermal and electrical injuries; less frequently, we care for patients such as this one, with large wounds of other causes, including skin diseases, most commonly toxic epidermal necrolysis or Stevens–Johnson syndrome. Although reactivation of HSV is not an infrequent finding in the burn population, it is typically localized to the perioral region of the face. HSV reactivation can be a cause of graft failure; however, even with the immune dysfunction seen after a major thermal injury, widespread dissemination of HSV as seen in this patient is extremely rare.
Our role with this patient was supportive care, wound care, and coordination of care.34 With respect to the wound care, our goals were to provide a comfortable dressing with antimicrobial properties. We used a nonadherent, silicone-based, permeable dressing known as Mepitel (Mölnlycke Health Care), which was covered with a dressing impregnated with nanocrystalline silver (Acticoat [Smith and Nephew]).35 Acticoat can be left in place for 3 days while silver particles are slowly released onto the wound surface, maintaining broad antimicrobial activity without an appreciable risk of antibiotic resistance.36
The burn team also provided supportive care, including proper nutrition and fluid intake and the administration of intravenous antibiotics. Culture of a surface-wound specimen obtained at the other hospital showed abundant S. aureus. Cultures of superficial wounds are often difficult to interpret, since surface swabs do not distinguish colonization from invasive infection. Therefore, we typically rely on topical antimicrobial agents, rather than systemic agents, to suppress bacterial counts on the wound surface. When clinical evidence suggests invasive infection, such as cellulitis or sepsis, more aggressive treatment with systemic antimicrobial agents is warranted. In this case, local antimicrobial agents were used initially.
On the fourth day, hypotension developed in the patient (systolic blood pressure, 70 mm Hg), the temperature rose to 39.0°C, and urine output decreased. She was transferred to the burn intensive care unit, and because of concern about a rapidly worsening course, the trachea was intubated and mechanical ventilation was begun. Treatment with broad-spectrum antibiotics (ciprofloxacin and aztreonam) was begun because of suspected sepsis. Blood cultures drawn the previous day grewPseudomonas aeruginosa. Refractory septic shock developed, with disseminated intravascular coagulation and progression to multiorgan failure, despite maximal medical efforts; cardiac arrest with pulseless electrical activity developed, and attempts at resuscitation were unsuccessful. The patient died on the fifth hospital day.


Dr. Nazarian: Skin sections obtained at the postmortem examination revealed areas of ulceration and cytopathic changes associated with herpesvirus, with intervening areas of intact skin with psoriasiform hyperplasia. Histopathological features of KVE evolve through stages, all of which were identified in this case. Intranuclear inclusions first appear in the basal layer of the epidermis, imparting a ground-glass appearance to the nucleus (Figure 3A
FIGURE 3Postmortem Examination of the Skin.
), with chromatin margination, nuclear molding, and cytoplasmic vacuolization.37Vesicle formation ensues as keratinocytes undergo balloon degeneration, multinucleation, and acantholysis (Figure 3B). The disease progresses to epithelial necrosis with “ghosts” of acantholytic multinucleated epithelial cells and ulceration (Figure 3C).37 There was extensive overgrowth of the wounds by gram-negative rods.
Immunohistochemical studies revealed positive staining of affected cells for both HSV-1 and HSV-2 antibodies (Figure 3D). These antibodies cross-react, and in the context of a positive direct fluorescent antibody test for HSV-1, these results are consistent with HSV-1 infection.
We were unable to obtain the slides from the skin biopsy performed 3 years earlier that reportedly revealed atopic dermatitis. Therefore, the nature of the underlying dermatosis in this case cannot be firmly established by pathological examination as either atopic dermatitis or psoriasis.
The remainder of the autopsy showed no evidence of cytopathic effect associated with herpesvirus in the visceral organs. Other findings included changes due to severe sepsis, including diffuse alveolar damage of the lungs, acute tubular necrosis, and anoxic damage to the brain; the presence of microthrombi in many organs was consistent with disseminated intravascular coagulation.
Dr. Eric S. Rosenberg (Pathology): Are there any questions?
Dr. Nancy Lee Harris (Pathology): In KVE, are the herpetic lesions usually confined to areas of skin affected by the underlying skin disease?
Dr. Mackool: Lesions of KVE typically begin in the area involved by the dermatitis but may spread during the course of the illness to previously uninvolved areas.


Kaposi's varicelliform eruption (eczema herpeticum) due to HSV-1 infection.
Gram-negative sepsis.
Presented at Dermatology Grand Rounds.
Disclosure forms provided by the authors are available with the full text of this article at
No potential conflict of interest relevant to this article was reported.
We thank Dr. David L. Hudacek (Internal Medicine) and Drs. Harry Ma and Shawn Fagan (Burn Surgery) for assistance with the preparation of the case history.


From the Department of Dermatology (B.T.M.); the Division of Burns, Department of Surgery (J.G.); and the Department of Pathology (R.M.N.), Massachusetts General Hospital; and the Departments of Dermatology (B.T.M.), Surgery (J.G.), and Pathology (R.M.N.), Harvard Medical School — both in Boston.

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